Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

作者：Valayannopoulos Vassili; Malinova Vera; Honzik Tomas; Balwani Manisha; Breen Catherine; Deegan Patrick B; Enns Gregory M; Jones Simon A; Kane John P; Stock Eveline O; Tripuraneni Radhika; Eckert Stephen; Schneider Eugene; Hamilton Gavin; Middleton Michael S; Sirlin Claude; Kessler Bruce; Bourdon Christopher; Boyadjiev Simeon A; Sharma Reena; Twelves Chris; Whitley Chester B; Quinn Anthony G^*

来源：Journal of Hepatology, 2014, 61(5): 1135-1142.

DOI：10.1016/j.jhep.2014.06.022

• Lysosomal storage
• Enzyme replacement
• Fatty liver
• Hepatomegaly
• Dyslipidemia

Background %26 Aims: Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. %26lt;br%26gt;Methods: Sebelipase alfa (1 mg/kg or 3 mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. %26lt;br%26gt;Results: 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient%26apos;s event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. %26lt;br%26gt;Conclusions: Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is under-way (ARISE: NCT01757184).

• 出版日期2014-11